Abstract |
Dysfunction of p53 is observed in many malignant tumors, which is related to cancer susceptibility. In cervical cancer, p53 is primarily degradated through the complex of high-risk human papillomaviruses (HPV) oncoprotein E6 and E6-associated protein (E6AP) ubiquitin ligase. What is less clear is the mechanism and role of murine double minute X (MDMX) in cervical carcinogenesis due to the inactive status of murine double minute 2 (MDM2). In the current study, XI-011 ( NSC146109), a small-molecule inhibitor of MDMX, showed robust anti-proliferation activity against several cervical cancer cell lines. XI-011 promoted apoptosis of cervical cancer cells via stabilizing p53 and activating its transcription activity. Moreover, XI-011 inhibited the growth of xenograft tumor in HeLa tumor-bearing mice, as well as enhanced the cytotoxic activity of cisplatin both in vitro and in vivo. Interestingly, MDMX co-localized with E6AP and seems to be a novel binding partner of E6AP to promote p53 ubiquitination. In conclusion, this work revealed a novel mechanism of ubiquitin-dependent p53 degredation via MDMX-E6AP axis in cervical carcinogenesis, and offered the first evidence that MDMX could be a viable drug target for the treatment of cervical cancer.
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Authors | Jingwen Zhang, Guohua Yu, Yanting Yang, Yingjie Wang, Mengqi Guo, Qikun Yin, Chunhong Yan, Jingwei Tian, Fenghua Fu, Hongbo Wang |
Journal | Pharmacological research
(Pharmacol Res)
Vol. 177
Pg. 106128
(03 2022)
ISSN: 1096-1186 [Electronic] Netherlands |
PMID | 35150860
(Publication Type: Journal Article)
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Copyright | Copyright © 2022 Elsevier Ltd. All rights reserved. |
Chemical References |
- Oncogene Proteins, Viral
- Tumor Suppressor Protein p53
- Ubiquitin
- Proto-Oncogene Proteins c-mdm2
- Ubiquitin-Protein Ligases
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Topics |
- Animals
- Carcinogenesis
- Female
- Humans
- Mice
- Oncogene Proteins, Viral
(metabolism)
- Proto-Oncogene Proteins c-mdm2
(metabolism)
- Tumor Suppressor Protein p53
(metabolism)
- Ubiquitin
(metabolism)
- Ubiquitin-Protein Ligases
(metabolism)
- Uterine Cervical Neoplasms
(drug therapy, pathology)
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